romidepsin plus oral 5-azacitidine in relapsed/refractory lymphoid malignancies

Conditions: Lymphoid Malignancies; Lymphoma; Hodgkin Lymphoma; Non-hodgkin Lymphoma

Summary: this is an open label, phase i/iia, 3 x 3 dose escalation study with an initial phase i followed by a disease focused phase ii. the primary objective of the phase i is to determine the maximum tolerated dose (mtd) and dose limiting toxicity (dlt) of the combinations of oral 5-azacitidine and romidepsin in patients with lymphoma. the safety and toxicity of this combination will be evaluated throughout the entire study. if the combination of oral 5-azacitidine and romidepsin is found to be feasible and an mtd is established, the phase ii part of the study will be initiated. phase ii will consist of a 2 stage design of the combination of oral 5-azacitidine and romidepsin for patients with relapsed or refractory t-cell lymphomas.

subjects will receive oral 5-azacitidine and romidepsin, administered as follows: oral 5-azacitidine from days 1-14 (dose cohorts -1 to 5) or days 1-21 (dose cohort 6); and romidepsin administered intravenously on days 8 (dose cohorts 1-4) of a 28 day cycle, and day 22 (dose cohorts 5 and 6) of a 35 day cycle. cohorts of 3 patients will be enrolled sequentially as outlined in the dose escalation scheme. once the mtd is reached the phase ii part of the protocol will be initiated in patients with t-cell lymphoma.

Eligibility criteria:
inclusion criteria: * phase i: histologically confirmed relapsed or refractory non-hodgkin lymphoma or hodgkin lymphoma (who criteria), with no accepted curative options. * phase ii: relapsed or refractory t-cell lymphoma, including patients with central nervous system (cns) involvement or lymphomatous meningitis are allowed on study. * relapsed or refractory disease following frontline chemotherapy. no upper limit for the number of prior therapies. patients may have relapsed after prior autologous or allogeneic stem cell transplant. * evaluable disease in the phase i, and measurable disease for the phase ii. * age \> or = 18 years. * eastern cooperative oncology group (ecog) performance status \< or = 2. * patients must have adequate organ and marrow function. * negative urine or serum pregnancy test for females of childbearing potential. * all females of childbearing potential must use an effective barrier method of contraception during the treatment period and for at least 1 month thereafter. male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter. * ability to understand and the willingness to sign a written informed consent document. exclusion criteria: * prior therapy * exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. * systemic steroids that have not been stabilized ( ≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs. * no other concurrent investigational agents are allowed. * history of allergic reactions to oral 5-azacitidine or romidepsin. * uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * pregnant women. * nursing women. * active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). if there is a history of prior malignancy, the patient must be disease-free for ≥ 3 years. * patients known to be human immunodeficiency virus (hiv)-positive. * patients with active hepatitis a, hepatitis b, or hepatitis c infection. * concomitant use of cyp3a4 inhibitors. * any known cardiac abnormalities.

Keywords: lymphoid malignancies lymphoma hodgkin lymphoma non-hodgkin lymphoma follicular lymphoma diffuse large b-cell lymphoma anaplastic large cell lymphoma chronic lymphocytic leukemia small lymphocytic lymphoma mantle cell lymphoma marginal zone lymphoma burkitt lymphoma waldenstrom macroglobulinemia peripheral t-cell lymphoma cutaneous t-cell lymphoma